All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein. A full list of these publications is included at the end of the specification, immediately preceding the claims.
The hallmark of HIV infection and the eventual cause of AIDS is the progressive destruction of the CD4 T cell population. The in vitro cytopathic effects of HIV, with the CD4 molecule as its receptor and the gp120 molecule of the HIV envelope as its ligand, have led to the notion that HIV is the direct cause for the destruction of the CD4 T cell population [Lifson, J D. et al. (1986) Science 232:1123-1126; Casella, C R. et al. (1997) Curr. Opin. Hematol. 4: 24-31; Gandhi, R T. et al. (1998) J. Exp. Med. 187:1113-1122]. The inventors and others have previously suggested that additional mechanisms must account for the CD4 T cell decline during HIV infection [Grossman, Z. et al. (1993) Clin. Immunol. Immunopathol. 69: 1-13; Anderson, R W. et al. (1998) JAIDS 17: 245-252; Margolick, J B. et al. (1995) Nat. Med. 1:674-680; Quibin, L. et al. (2001) JAIDS 27:389-397] since the number of HIV infected cells at any stage of the infection is too small to account for the massive destruction of CD4 cells. One of the possible mechanisms that have been suggested is the killing of CD4 T cells by autologous CD8 T cells, with the CD4 molecules as self-antigens and targets for this autoimmune activity [Israël-Biet, D. et al. (1990) Clin. Exp. Immunol. 81:18-24; Zarling, J M. et al. (1992) J. Immunol. 144:2992-2998; Caporossi, A P. et al. (1998) Virol. Immunol. 11: 9-17]. Indeed, CD8 T cells of HIV-infected subjects were found to kill both HIV infected and non-infected CD4 T cells [Zarling (1992) id ibid.; Salemi, S. et al. (1995) J. Exp. Med. 81:2253-2257]. HIV infection could therefore be seen as an inducer for an autoimmune response against the CD4 molecule, leading to the destruction of the CD4 T-cell population [Lanzavecchia, A. (1995) J. Exp. Med. 181:1945-1948; Grant, M D. et al. (1994) JAIDS 7:571-579]. Such an autoimmune process could account for the persistence of CD4 T-cell leukopenia in patients despite complete or partial HIV viral suppression by highly active anti-retroviral treatment (HAART). Unfortunately, the proportion of such patients without sufficient immunological response is significant, reaching 50-60% in a number of reported series [Grabar, S. et al. (2000) Ann. Intern. Med. 133:410-410; Tarwater, P M. et al. (2001) JAIDS, 168-175; Pitrak, D L. et al. (2001) AIDS 15:1317-1319; Carcelane, G. et al. (2001) Curr. Opin. Immunol. 13:479-482; Kaufmann, G. R. et al. (2003) Arch. Intern. Med. 163:2187-95].
T cell vaccination (TCV) has been studied in experimental animals [Ben-Nun, A. et al. (1981) Nature 292:60-61; Holoshits, J. et al. (1983) J. Immunol. 131:2810-2813; Lider, O. et al. (1988) Science 239: 181-183] and lately has been used clinically to induce the down-regulation of autoimmune diseases such as multiple sclerosis [Van Laar, J M. et al. (1993) J. Autoimmunity 6:159-167; Haffler, D A. et al. (1992) Clin. Immunol. Immunopathol. 62: 307-317; Zhang, J. et al. (1993) Science 262: 1451-1454; Zhang, J. et al. (2000) J. Immunol. 164:4011-4017]. In all these instances, it was designed to raise an immune response in the host against the autologous effector cells that are causing the pathological changes responsible for the autoimmune disease. When successful, TCV has resulted in the suppression of these effector cells by the host response to the T cell vaccines, and the disease was either prevented or ameliorated. Based on the hypothesis that an autoimmune process takes place during HIV infection, Atlan and colleagues have suggested that autologous anti-CD4 T cells might be used as vaccines to down-regulate anti-CD4 autoimmunity in HIV-infected patients [Atlan, H. et al. (1993) Immunol. Today 14:200-202; Atlan, H. et al. (1994) Res. Immunol. 145: 165-183; Atlan, H. and Cohen, I R. (1996) Immunology of HIV Infection. New York: Plenum Press, Ch. 28].
Despite all the hypotheses that were raised in this respect, no studies have been done so far, at the clinical level, in order to verify the cellular origin of the immunodeficiency observed in HIV-infected individuals. The present study is the first of its kind in identifying one of the main causes of CD4+ T-cell depletion during HIV infection. The inventors investigated whether an autoimmune reaction towards CD4 is present in HIV infected patients, in comparison to controls. CD4-recognizing CD8 cells were found circulating and functional in HIV-infected patients, and such reactivity was evidenced in most of the HIV infected individuals. Thus, the present inventors propose and prove possible the generation and the use of inactivated CD4-specific CD8 cells as a tailor-made vaccine for treating HIV-induced immunodeficiency. In this context, the inventors went one step further and performed an open trial of the TCV developed herein in HIV-infected individuals. Results are summarized in Example 1 below. Based on the encouraging results of this study, the inventors developed a general outline for a T-cell vaccination protocol.
Thus, it is an object of the present invention to provide a method for preparing T cell vaccines tailored for immunodeficient patients, particularly when the immunodeficiency is consequent of HIV infection. The invention also provides a method of treatment of an auto-immune process induced by HIV infection. To a larger scale, the invention provides a T-cell vaccination protocol, based on the tailored-made T cell vaccines prepared from HIV-infected individuals.